Tumor Necrosis Factor Receptor–Associated Factor 6 Promotes Hepatocarcinogenesis by Interacting With Histone Deacetylase 3 to Enhance c-Myc Gene Expression and Protein Stability (Hepatology 2019)

報告日期: 2021/03/12
報告時間: 15:10/16:00
報告學生: 陳昱志(以英文報告)
講評老師: 黃溫雅
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Tumor Necrosis Factor Receptor-Associated Factor 6 Promotes Hepatocarcinogenesis by Interacting with Histone Deacetylase 3 to Enhance c-Myc Gene Expression and Protein Stability

Hua Wu, et al. Hepatology, VOL. 0, NO. 0, 2019

Speaker: Yu-Chih Chen                                     Time: 2021/03/12 15:10-16:00

Commentator: Dr. Wen-Ya Huang                      Place: Room 602, College of Medicine

Abstract:

In hepatocellular carcinoma (HCC), irregulated c-Myc is positively correlated with tumor growth and progression.[1] In this paper, the authors demonstrated that tumor necrosis factor receptor-associated factor 6 (TRAF6), an E3 ligase, regulates c-Myc expression and stability through mediating the ubiquitination of histone deacetylase 3 (HDAC3). First, the authors showed that high TRAF6 expression was positively correlated with unfavorable prognosis and tumor growth, which indicated TRAF6 functions as an oncogene in HCC. Also, they found that TRAF6 induces c-Myc expression through ubiquitinating HDAC3 to promote H3K9 acetylation. Moreover, TRAF6 binds E402 of HDAC3 via TRAF-C domain and ubiquitinates K422 of HDAC3 through K63-linkage ubiquitination. Next, the authors surprisingly found that HDAC3 can deacetylate c-Myc and c-Myc acetylation can inhibit carboxyl terminus of heat shock cognate 70-kDa-interacting protein (CHIP)-induced ubiquitination, which is mentioned as an E3 ligase to ubiquitinate c-Myc before.[2] Consequently, TRAF6 stabilizes c-Myc through inhibiting HDAC3 deacetylation and CHIP-induced ubiquitination. Nevertheless, the authors validated the mechanism of TRAF6/HDAC3/c-Myc signaling pathway in vivo and discover that inhibition of TRAF6 can efficiently impair tumor growth. Taken together, TRAF6 promotes c-Myc expression through ubiquitinating HDAC3 to avoid H3K9 acetylation while TRAF6 also stabilizes c-Myc via ubiquitinating HDAC3 to keep c-Myc acetylation and prevent CHIP-induced ubiquitination. Eventually, TRAF6/HDAC3/c-Myc signaling pathway can promote hepatocarcinogenesis. These findings indicate that TRAF6 can bypass NF-κB signaling pathway, which is considered as the central player in HCC [3] to induce c-Myc expression and stability.

References:

  1. Kuzyk, A. and S. Mai, c-MYC-induced genomic instability. Cold Spring Harb Perspect Med, 2014. 4(4): p. a014373.
  2. Paul, I., et al., The ubiquitin ligase CHIP regulates c-Myc stability and transcriptional activity. Oncogene, 2013. 32(10): p. 1284-95.
  3. Pikarsky, E., et al., NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature, 2004. 431(7007): p. 461-6.